Design, Synthesis, and Pharmacological Evaluation of Dual FXR-LIFR Modulators for the Treatment of Liver Fibrosis.

Although multiple approaches have been suggested, treating mild-to-severe fibrosis in the context of metabolic dysfunction associated with liver disease (MASLD) remains a challenging area in drug discovery. Pathogenesis of liver fibrosis is multifactorial, and pathogenic mechanisms are deeply intertwined; thus, it is well accepted that future treatment requires the development of multitarget modulators. Harnessing the 3,4,5-trisubstituted isoxazole scaffold, previously described as a key moiety in Farnesoid X receptor (FXR) agonism, herein we report the discovery of a novel class of hybrid molecules endowed with dual activity toward FXR and the leukemia inhibitory factor receptor (LIFR). Up to 27 new derivatives were designed and synthesized. The pharmacological characterization of this series resulted in the identification of 3a as a potent FXR agonist and LIFR antagonist with excellent ADME properties. In vitro and in vivo characterization identified compound 3a as the first-in-class hybrid LIFR inhibitor and FXR agonist that protects against the development of acute liver fibrosis and inflammation.

A label free chemoproteomic-based platform to disclose cannabidiol molecular mechanism of action on chronic myelogenous leukemia cancer cells.

The discovery of the interactome of cannabidiol (CBD), a non-psychoactive cannabinoid from Cannabis sativa L., has been here performed on chronic myelogenous leukemia cancer cells, using an optimized chemo-proteomic stage, which links Drug Affinity Responsive Target Stability with Limited Proteolysis Multiple Reaction Monitoring approaches. The obtained results showed the ability of CBD to target simultaneously some potential protein partners, corroborating its well-known poly-pharmacology activity. In human chronic myelogenous leukemia K562 cancer cells, the most fascinating protein partner was identified as the 116 kDa U5 small nuclear ribonucleoprotein element called EFTUD2, which fits with the spliceosome complex. The binding mode of this oncogenic protein with CBD was clarified using mass spectrometry-based and in silico analysis.

Expanding the Library of 1,2,4-Oxadiazole Derivatives: Discovery of New Farnesoid X Receptor (FXR) Antagonists/Pregnane X Receptor (PXR) Agonists.

Compounds featuring a 1,2,4-oxadiazole core have been recently identified as a new chemotype of farnesoid X receptor (FXR) antagonists. With the aim to expand this class of compounds and to understand the building blocks necessary to maintain the antagonistic activity, we describe herein the synthesis, the pharmacological evaluation, and the in vitro pharmacokinetic properties of a novel series of 1,2,4-oxadiazole derivatives decorated on the nitrogen of the piperidine ring with different N-alkyl and N-aryl side chains. In vitro pharmacological evaluation showed compounds 5 and 11 as the first examples of nonsteroidal dual FXR/Pregnane X receptor (PXR) modulators. In HepG2 cells, these compounds modulated PXR- and FXR-regulated genes, resulting in interesting leads in the treatment of inflammatory disorders. Moreover, molecular docking studies supported the experimental results, disclosing the ligand binding mode and allowing rationalization of the activities of compounds 5 and 11.